Journal Article

CFAP45 deficiency causes situs abnormalities and asthenospermia by disrupting an axonemal adenine nucleotide homeostasis module

Dzeja, Petras P., Ta-Shma, Asaf, Ueffing, Marius, Katsanis, Nicholas, Kaiser, Thomas, Memari, Yasin, Horn, Nicola, Shiratori, Hidetaka, Große-Onnebrink, Jörg, Ikawa, Yayoi, Pang, Yuan-Ping, Praveen, Kavita, Mizuno, Katsutoshi, Nöthe-Menchen, Tabea, Rabert, Franziska, Olbrich, Heike, Twan, Wang Kyaw, Minegishi, Katsura, Hamada, Hiroshi, Cindrić, Sandra, Stumme, Friederike, Letteboer, Stef J., Hjeij, Rim, Höben, Inga M., Dworniczak, Bernd, Elpeleg, Orly, Takaoka, Katsuyoshi, Junger, Katrin, Aviram, Micha, Klinkenbusch, Judith A., Dougherty, Gerard W., Bartscherer, Kerstin, Pennekamp, Petra, Biebach, Luisa, Gützlaff, Jana, Omran, Heymut, Aprea, Isabella, Davis, Erica E., Boldt, Karsten, Strünker, Timo, Werner, Claudius, Young, Samuel, Loges, Niki T., Bracht, Diana C., Raidt, Johanna, Mussaffi, Huda, Wallmeier, Julia, Ide, Takahiro, Perles, Zeev, Amirav, Israel, Roepman, Ronald

2020

Overview

Axonemal dynein ATPases direct ciliary and flagellar beating via adenosine triphosphate (ATP) hydrolysis. The modulatory effect of adenosine monophosphate (AMP) and adenosine diphosphate (ADP) on flagellar beating is not fully understood. Here, we describe a deficiency of cilia and flagella associated protein 45 ( CFAP45 ) in humans and mice that presents a motile ciliopathy featuring situs inversus totalis and asthenospermia. CFAP45-deficient cilia and flagella show normal morphology and axonemal ultrastructure. Proteomic profiling links CFAP45 to an axonemal module including dynein ATPases and adenylate kinase as well as CFAP52 , whose mutations cause a similar ciliopathy. CFAP45 binds AMP in vitro, consistent with structural modelling that identifies an AMP-binding interface between CFAP45 and AK8. Microtubule sliding of dyskinetic sperm from Cfap45 −/− mice is rescued with the addition of either AMP or ADP with ATP, compared to ATP alone. We propose that CFAP45 supports mammalian ciliary and flagellar beating via an adenine nucleotide homeostasis module. The mechanism by which adenosine monophosphate modulates dynein ATPase-mediated ciliary and flagellar beating remains obscure. Here the authors identify an axonemal module including cilia and flagella associated protein 45 that supports adenine nucleotide homeostasis and underlies a human ciliopathy

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 101/28 / 14/19 / 14/28 / 45/23 / 631/208 / 64/110 / 692/699 / 82/1 / 82/111 / 82/29 / 82/47 / 82/51 / 82/58 / 82/80 / 82/83 / Abnormalities / Adenine / Adenosine diphosphate / Adenosine monophosphate / Adenosine triphosphatase / Adenosine triphosphate / Adenylate kinase / AMP / ATP / Cilia / Dynein / Flagella / Homeostasis / Humanities and Social Sciences / Inversion / Kinases / Modules / Morphology / multidisciplinary / Mutation / Nucleotides / Proteins / Science / Science (multidisciplinary) / Ultrastructure